Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor

In aged rodents, impairments in learning and memory have been associated with an age-dependent decline in forebrain of cholinergic function1, and recent evidence indicates that the cholinergic neurons in the nucleus basalis magnocellularis, the septal-diagonal band area and the striatum undergo age-dependent atrophy2–5. Thus, as in Alzheimer-type dementia in man, degenerative changes in the forebrain cholinergic system may contribute to age-related cognitive impairments in rodents. The cause of these degenerative changes is not known. Recent studies have shown that the central cholinergic neurons in the septal–diagonal band area, nucleus basalis and striatum are sensitive to the neurotrophic protein nerve growth factor (NGF)6–10. In particular, intraventricular injections or infusions of NGF in young adult rats have been shown to prevent retrograde neuronal cell death11–13 and promote behavioural recovery after damage to the septo–hippocampal connections14. It is so far not known, however, whether the atrophic cholinergic neurons in aged animals are responsive to NGF treatment. We report here that continuous intracerebral infusion of NGF over a period of four weeks can partly reverse the cholinergic cell body atrophy and improve retention of a spatial memory task in behaviourally impaired aged rats.